Efficacy and safety of immune checkpoint inhibitors (ICI) for the treatment of metastatic penile squamous cell carcinoma (mPSCC).

4 Background: Metastatic penile squamous cell carcinoma (mPSCC) is a rare and aggressive malignancy with limited treatment options. Standard systemic therapies include paclitaxel, ifosfamide, cisplatin (TIP), fluorouracil and cisplatin (5-FU + cis), paclitaxel monotherapy and cetuximab. These regimens were evaluated as small single-arm studies. The HERCULES trial, a single-arm phase 2 clinical study, demonstrated the safety and efficacy of combining immunotherapy with chemotherapy, signaling a potential benefit of immunotherapy. Our retrospective analysis evaluates the safety and efficacy of single-agent immunotherapy at the University of Kansas and Aurora St. Luke’s Medical Center. Methods: We conducted a multicenter retrospective, IRB-approved study of mPSCC patients treated with single-agent immunotherapy from 2015 to 2023. Objective response rates were assessed per RECIST version 1.1, and progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Adverse events were graded per CTCAE version 5.0, with only grade 3+ immune-related adverse events being recorded. Results: Nine patients with mPSCC were included, with a median age of 75 years (range, 50-92). Over half (n=5) had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 2 or more, and most (n=8) had visceral metastasis. Single-agent immunotherapy was administered as first-line (n=3), second-line (n=4), and third-line or beyond (n=2). Pembrolizumab was used in six patients, with two receiving nivolumab and one cemiplimab. The objective response rate was 33.3% (n=3), including one complete response. Median PFS was 2.82 months (range, 1.0-14.3), and median OS was 4.3 months (range, 1.0-24.9). Patients who responded had PFS exceeding 12 months, with two still ongoing at data cutoff. No grade 3 or higher treatment-related adverse event has been observed during the treatment period. Additional analyses to correlate the response with HPV positivity are ongoing. Conclusions: Our findings suggest that single-agent immunotherapy can yield favorable response rates and durations in older and/or frail mPSCC patients. While our sample size is small and retrospective, response rates are comparable to those in the HERCULES trial (33.3% vs. 39.4% with chemoimmunotherapy). Notably, grade 3+ treatment-related adverse events were lower in our study compared to 51.4% of HERCULES patients. This underscores the potential of single-agent immunotherapy as a safe and effective option for this rare malignancy. Further prospective studies are needed to optimize treatment strategies for mPSCC.